This invention relates to a series of substituted xcex1-aminosulphonyl-acetohydroxamic acids which are inhibitors of zinc-dependent metalloprotease enzymes. In particular, the compounds are inhibitors of certain members of the matrix metalloprotease (MMP) family.
Matrix metalloproteases (MMPs) constitute a family of structurally similar zinc-containing metalloproteases, which are involved in the remodelling and degradation of extracellular matrix proteins, both as part of normal physiological processes and in pathological conditions. Since they have high destructive potential, MMPs are usually under close regulation and failure to maintain MMP regulation has been implicated as a component of a number of diseases and conditions including pathological conditions, such as atherosclerotic plaque rupture, heart failure, restenosis, periodontal disease, tissue ulceration, cancer metastasis, tumour angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells.
Another important function of certain MMPs is to activate various enzymes, including other MMPs, by cleaving the pro-domains from their protease domains. Thus some MMPs act to regulate the activities of other MMPs, so that over-production of one MMP may lead to excessive proteolysis of extracellular matrix by another. Moreover, MMPs have different substrate preferences (shown in the following Table for selected family members) and different functions within normal and pathological conditions. For recent reviews of MMPs, see Current Pharmaceutical Design, 1996, 2, 624 and Exp. Opin. Ther. Patents, 1996, 6 1305.
Excessive production of MMP-3 is thought to be responsible for pathological tissue breakdown which underlies a number of diseases and conditions. For example, MMP-3 has been found in the synovium and cartilage of osteoarthritis and rheumatoid arthritis patients, thus implicating MMP-3 in the joint damage caused by these diseases: see Biochemistry, 1989, 28, 8691 and Biochem. J., 1989, 258, 115. MMP-13 is also thought to play an important role in the pathology of osteoarthritis and rheumatoid arthritis: see Lab. Invest., 1997, 76, 717 and Arthritis Rheum., 1997, 40, 1391.
The over-expression of MMP-3 has also been implicated in the tissue damage and chronicity of chronic wounds, such as venous ulcers, diabetic ulcers and pressure sores: see Brit. J. Dermatology, 1996, 135, 52. Collagenase-3 (MMP-13) has also recently been implicated in the pathology of chronic wounds (J Invest Dermatol, 1997, 109, 96-101).
Furthermore, the production of MMP-3 may also cause tissue damage in conditions where there is ulceration of the colon (as in ulcerative colitis and Crohn""s disease: see J. Immunol., 1997 158, 1582 and J. Clin. Pathol., 1994, 47, 113) or of the duodenum (see Am. J. Pathol., 1996, 148, 519).
Moreover, MMP-3 is also thought to be involved in skin diseases such as dystrophic epidermolysis bullosa (see Arch. Dermatol. Res., 1995, 287, 428) and dermatitis herpetiformis (see J. Invest. Dermatology, 1995, 105, 184).
Rupture of atherosclerotic plaques by MMP-3 has also been described (see e.g. Circulation, 1997, 96, 396). Thus, MMP-3 inhibitors may find utility in the treatment of conditions caused by or complicated by embolic phenomena such as cardiac or cerebral infarctions.
Studies of human cancers have shown that MMP-2 is activated on the invasive tumour cell surface (see J. Biol. Chem., 1993, 268, 14033) and BB-94, a non-selective peptidic hydroxamate MMP inhibitor, has been reported to decrease the tumour burden and prolong the survival of mice carrying human ovarian carcinoma xenografts (see Cancer Res., 1993, 53, 2087). Various series of MMP inhibitors have appeared in the literature which have a carbonyl moiety (CO) and a sulphone moiety (SO2) with a two atom xe2x80x9cspacerxe2x80x9d interposed between them. For example, xcex1-arylsulphonamido-substituted acetohydroxamic acids are disclosed in EP-A-0606046, WO-A-9627583 and WO-A-9719068, whilst EP-A-0780386 discloses certain related sulphone-substituted hydroxamic acids.
The compounds of the present invention represent a new class of compounds, and are inhibitors of some of the members of the MMP family. In particular, they are inhibitors of MMP-3 and/or MMP-13, with certain compounds exhibiting varying degrees of selectivity over other MMPs, such as MMP-1, MMP-2, MMP-9 and MMP-14. Thus they may be of utility in treating diseases and conditions mediated by MMPs, in particular MMP-3 and/or MMP-13.
A series of substances related to the instant invention were disclosed in International Patent Application number publication no. WO 99/29667, herein incorporated by reference in its entirety.
According to one aspect of the present invention (xe2x80x9cAxe2x80x9d), there is provided a compound of formula (I): 
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond,
X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene, pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is H, C1-4 alkyl optionally substituted by C1-4 alkoxy, NR4R5 or OH, or R is C1-4 alkoxy optionally substituted by 1 or 2 substituents selected from (C1-4 alkyl optionally substituted by OH), C1-4 alkoxy, OH and NR4R5;
R1 and R2 are each independently H, C1-6 alkyl optionally substituted by OH or C1-4 alkoxy, or C2-6 alkenyl;
or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO2 and NR6, and which 3- to 7-membered ring is optionally substituted by one or more OH;
R3 is H, halo, methyl, or methoxy;
R4 and R5 are each independently H or C1 to C6 alkyl optionally substituted by OH, C1 to C4 alkoxy or aryl,
or R4 and R5 can be taken together with the N atom to which they are attached, to form a 3- to 7-membered ring, optionally incorporating a further hetero-moiety selected from O, S, SO2 and NR7; and
R6 and R7 are each independently H or C1 to C4 alkyl.
According to a further aspect of the invention (xe2x80x9cBxe2x80x9d), there is provided a compound of formula (I): 
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond;
X is a monocyclic aromatic linker moiety selected from pyrazolylene, thiazolylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is H, C1-4 alkyl optionally substituted by C1-4 alkoxy or NR4R5 or OH, or C1-4 alkoxy optionally substituted by 1 or 2 substituents selected from (C1-4 alkyl optionally substituted by OH), C1-4 alkoxy, OH and NR4NR5;
R1 and R2 are each independently H, C1-6 alkyl optionally substituted by OH or C1-4 alkoxy, or C2-6 alkenyl;
or R1 and R2 are taken, together with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO2 and NR6, and which 3- to 7-membered ring is optionally substituted by one or more OH;
R3 is H, halo, methyl, or methoxy;
R4 and R5 are each independently H or C1 to C6 alkyl optionally substituted by OH, C1 to C4 alkoxy or aryl,
or R4 and R5 can be taken together with the N atom to which they are attached, to form a 3- to 7-membered ring, optionally incorporating a further hetero-moiety selected from O, S, SO2 and NR7; and
R6 and R7 are each independently H or C1 to C4 alkyl.
According to a further aspect of the invention (xe2x80x9cCxe2x80x9d) there is provided a compound of formula (I): 
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond;
X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene, pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is C1-4 alkyl substituted by NR4R5, C1-4 alkoxy substituted by NR4R5, or C1-4 alkoxy substituted by 2 substituents selected from (C1-4 alkyl optionally substituted by OH), C1-4 alkoxy, OH and NR4R5;
R1 and R2 are each independently H, C1-6 alkyl optionally substituted by OH or C1-4 alkoxy, or C2-6 alkenyl;
or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO2 and NR6, and which 3- to 7-membered ring is optionally substituted by one or more OH;
R3 is H, halo, methyl, or methoxy;
R4 and R5 are each independently H or C1 to C6 alkyl optionally substituted by OH, C1 to C4 alkoxy or aryl,
or R4 and R5 can be taken together with the N atom to which they are attached , to form a 3- to 7-membered ring, optionally incorporating a further hetero-moiety selected from O, S, SO2 and NR7; and
R6 and R7 are each independently H or C1 to C4 alkyl.
According to a further aspect of the invention (xe2x80x9cDxe2x80x9d) there is provided a compound of formula (I): 
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond,
X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene, pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is H, C1-4 alkyl optionally substituted by C1-4 alkoxy, NR4R5 or OH, or C1-4 alkoxy optionally substituted by 1 or 2 substituents selected from (C1-4 alkyl optionally substituted by OH), C1-4 alkoxy, OH and NR4R5;
R1 and R2 are each independently C1-6 alkyl substituted by OH;
or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO2 and NR6, and which 3- to 7-membered ring is substituted by one or more OH;
R3 is H, halo, methyl, or methoxy;
R4 and R5 are each independently H or C1 to C6 alkyl optionally substituted by OH, C1 to C4 alkoxy or aryl,
or R4 and R5 can be taken together with the N atom to which they are attached, to form a 3- to 7-membered ring, optionally incorporating a further hetero-moiety selected from O, S, SO2 and NR7; and
R6 and R7 are each independently H or C1 to C4 alkyl.
In all the above definitions A, B, C and D, unless otherwise indicated, alkyl, alkenyl, alkoxy, etc. groups having three or more carbon atoms may be straight chain or branched chain.
All the compounds of formula (I) in aspects A, B, C and D above may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formula (I) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof An individual enantiomer of a compound of formula (I) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active base or acid, as appropriate to the specific compound to be resolved. Furthermore, compound of formula (I) which contain alkenyl groups can exist as cis- or trans-geometric isomers. Again, the invention includes both the separated individual geometric isomers as well as mixtures thereof. Certain of the compounds of formula (I) may be tautomeric and all possible tautomers are included in the scope of this invention. Certain of the compounds of formula (I) may exhibit zwitterionic behaviour and all possible zwitterions are included in the scope of this invention. Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The pharmaceutically acceptable salts of all the compounds of the formula (I) include the acid addition and the base salts thereof. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means suitable for use in human or non-human animal medicine.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples include the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples include the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, tris, meglumine, choline, olamine, diolamine, ethylenediamine, benethamine, benzathene, glucosamine, nicotinamide, ornithine, guanidine, guanine, arginine and procaine salts.
For a review on suitable salts see for example Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
Solvates (e.g. hydrates) of the compounds and salts of aspects A, B, C and D of the invention are included in the invention. In some cases, the solvate may be the direct product of a reaction to make a compound or salt of the invention in a solvent, in which case no further transformation step would be necessary. In other cases, solvates may be made by methods known in the art, such as by crystallisation from a solvent.
Prodrugs of the compounds of aspects A, B, C and D of the invention, their pharmaceutically acceptable salts and solvates thereof, are also envisaged by the invention. For reference as to how to prepare prodrugs, see standard texts in this field, for example xe2x80x9cDesign of Prodrugsxe2x80x9d ed. H. Bundgaard (1985, Elsevier, Amsterdam/New York/Oxford).
For aspects C and D of the invention, X is preferably phenylene, pyridinylene, pyrazolylene or thiazolylene.
For aspects C and D of the invention, X is more preferably 1,3-phenylene, 2,6-pyridinylene, 1,3-pyrazolylene or 2,5-thiazolylene.
For aspect B of the invention X is preferably pyrazolylene or thiazolylene. For aspect B of the invention X is more preferably 1,3-pyrazolylene or 2,5-thiazolylene.
For aspects B and D of the invention R is preferably H, methoxy, O(CH2)2OH, O(CH2)2OCH3, O(CH2)2N(CH3)2, O(CH2)2NHCH3, O(CH2)2NH2, CH2NHCH3, morpholinomethyl, 2-morpholinoethoxy, 2R-2,3-dihydroxy-1-propyloxy, 2S-2,3-dihydroxy-1-propyloxy or 1,3-dihydroxy-2-propyloxy. For aspects B and D of the invention R is most preferably O(CH2)2OH or O(CH2)2NH2.
For aspect C of the invention R is preferably O(CH2)2N(CH3)2, O(CH2)2NHCH3, O(CH2)2NH2, CH2NHCH3, morpholinomethyl, 2-morpholinoethoxy, 2R-2,3-dihydroxy-1-propyloxy, 2S-2,3-dihydroxy-1-propyloxy or 1,3-dihydroxy-2-propyloxy. For aspect C of the invention R is most preferably O(CH2)2NH2.
For aspects B and C of the invention preferably R1 and R2 are each independently C1-6 alkyl optionally substituted by OH, or R1 and R2 are taken together, with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO2 and NR6, and which 3- to 7-membered ring is optionally substituted by one or more OH. For aspects B and C of the invention more preferably R1 and R2 are each CH3, or R1 and R2 are taken together, with the C atom to which they are attached, to form a tetrahydropyran-4-ylidene, piperidin-4-ylidene, 1-methylpiperidin-4-ylidene, or 3,4-dihydroxycyclopentylidene moiety. For aspects B and C of the invention, yet more preferably R1 and R2 are taken together, with the C atom to which they are attached, to form a tetrahydropyran-4-ylidene, cis-3,4-dihydroxycyclopentylidene, trans-3,4-dihydroxycyclopentylidene or piperidin-4-ylidene moiety. For aspects B and C of the invention, most preferably R1 and R2 are taken together, with the C atom to which they are attached, to form a tetrahydropyran-4-ylidene, piperidin-4-ylidene, or cis-3,4-dihydroxycyclopentylidene where the hydroxy substituents have a cis-relationship to the hydroxamate moiety.
For aspect D of the invention, R1 and R2 are preferably taken together, with the C atom to which they are attached, to form a 3,4-dihydroxycyclopentylidene moiety. For aspect D of the invention, most preferably R1 and R2 are taken together, with the C atom to which they are attached, to form a cis-3,4-dihydroxycyclopentylidene group where the hydroxy substituents have a cis-relationship to the hydroxamate moiety.
For aspects A, B, C and D of the invention R3 is preferably methyl.
A preferred group of substances are those selected from the compounds of the Examples and the pharmaceutically acceptable salts and solvates thereof, especially the compounds of Examples 3, 6 and 14 below, and salts and solvates thereof.
The invention further provides synthetic methods for the production of compounds, salts and solvates of the invention, which are described below and in the Examples. The skilled man will appreciate that the compounds and salts of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein. Specific art which may be mentioned includes WO 99/29667, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d by R C Larock, VCH Publishers Inc. (1989), xe2x80x9cAdvanced Organic Chemistryxe2x80x9d by J March, Wiley Interscience (1985), xe2x80x9cDesigning Organic Synthesisxe2x80x9d by S Warren, Wiley Interscience (1978), xe2x80x9cOrganic Synthesisxe2x80x94The Disconnection Approachxe2x80x9d by S Warren, Wiley Interscience (1982), xe2x80x9cGuidebook to Organic Synthesisxe2x80x9d by R K Mackie and D M Smith, Longman (1982), xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T W Greene and P G M Wuts, John Wiley and Sons Inc. (1999), and P J Kocienski, in xe2x80x9cProtecting Groupsxe2x80x9d, Georg Thieme Verlag (1994), references therein, and any updated versions of the aforementioned standard works.
Where desired or necessary, the compound of formula (I) can be converted into a pharmaceutically acceptable salt thereof, conveniently by mixing together solutions of a compound of formula (I) and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration, or may be collected by other means such as by evaporation of the solvent. In some cases, the salt may be the direct product of a reaction to make a compound or salt of the invention in a solvent, in which case no further transformation step would be necessary.
It is to be understood that the synthetic transformation methods mentioned herein may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T W Greene and P G M Wuts, John Wiley and Sons Inc (1999).
The following methods are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
In the synthetic methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I) as defined above with respect to aspects A, B, C and D.
A compound of formula (I) may be prepared directly from a corresponding acid or acid derivative of formula (II): 
where Z is chloro, bromo, iodo, C1-3 alkyloxy or HO.
When prepared directly from the ester of formula (II), where Z is C1-3 alkyloxy, the reaction may be carried out by treatment of the ester with hydroxylamine, preferably up to a 3-fold excess of hydroxylamine, in a suitable solvent at from about room temperature to about 85xc2x0 C. The hydroxylamine is conveniently generated in situ from a suitable salt such as its hydrochloride salt by conducting the reaction in the presence of a suitable base such as an alkali metal carbonate or bicarbonate, e.g. potassium carbonate. Preferably the solvent is a mixture of methanol and tetrahydrofuran and the reaction is temperature is from about 65 to 70xc2x0 C.
Alternatively, the ester (II, where Z is C1-3 alkyloxy) may be converted by conventional hydrolysis to the corresponding carboxylic acid (II, Z is HO) which is then transformed to the required hydroxamic acid of formula (I). [If the R, R1 or R2 moieties contain any free hydroxyl groups, these should be protected with groups inert to this functional group interconversion reaction sequence, and released following it, using standard methodology.]
Preferably the hydrolysis of the ester is effected under basic conditions using about 2- to 6-fold excess of an alkali metal hydroxide in aqueous solution, optionally in the presence of a co-solvent, at from about room temperature to about 85xc2x0 C. Typically the co-solvent is a mixture of methanol and tetrahydrofuran or a mixture of methanol and 1,4-dioxan and the reaction temperature is from about 40 to about 70xc2x0 C.
The subsequent coupling step may be achieved using conventional amide-bond forming techniques, e.g. via the acyl halide derivative (II, Z is Cl, I or Br) and hydroxylamine hydrochloride in the presence of an excess of a tertiary amine such as triethylamine or pyridine to act as acid-scavenger, optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at from about 0xc2x0 C. to about room temperature. For convenience, pyridine may also be used as the solvent. Such acyl halide substrates are available from the corresponding acid via conventional methods.
In particular, any one of a host of amino acid coupling variations may be used. For example, the acid of formula (II) wherein Z is HO may be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (often referred to as xe2x80x9cwater-soluble carbodiimidexe2x80x9d or xe2x80x9cWSCDIxe2x80x9d) optionally in the presence of 1-hydroxybenzotriazole or 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (HOAt) and/or a catalyst such as 4-dimethylaminopyridine, or by using HOAt or a halotrisaminophosphonium salt such as bromotris(pyrrolidino)-phosphonium hexafluorophosphate. Either type of coupling is conducted in a suitable solvent such as dichloromethane, N-methylpyrrolidine (NMP)or dimethylformamide (DMF), optionally in the presence of pyridine or a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the hydroxylamine or the activating reagent is presented in the form of an acid addition salt), at from about 0xc2x0 C. to about room temperature. Typically, from 1.1 to 2.0 molecular equivalents of the activating reagent and from 1.0 to 4.0 molecular equivalents of any tertiary amine present are employed.
Preferred reagents for mediating the coupling reaction are HOAt, WSCDI and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU).
Preferably a solution of the acid (II, Z is HO) and N-ethyldiisopropylamine in a suitable solvent such as anhydrous dimethylformamide or anhydrous 1-methylpyrrolidin-2-one, under nitrogen, is treated with up to a 1.5-fold excess of HATU at about room temperature followed, after about 15 to 30 minutes, with up to about a 3-fold excess of hydroxylamine hydrochloride and up to about a 4-fold excess of N-ethyldiisopropylamine, optionally in the same solvent, at the same temperature.
More preferably the acid (II, Z is HO) is reacted with a carbodiimide, HOBt and hydroxylamine hydrochloride in pyridine in a suitable co-solvent such as dichloromethane.
An ester of formula (II, Z is C1-3 alkyloxy) may be prepared from an appropriate amine of formula (III) by sulphonylation with an appropriate compound of formula (IV), wherein R10 is C1-3 alkyloxy and Z1 is a leaving group such as Br, I or Cl. 
Preferably, Z1 is chloro.
The reaction may be effected in the presence of an appropriate base in a suitable solvent at from about 0xc2x0 C. to about room temperature. For example, when both R1 and R2 are hydrogen, an appropriate base is 1,8-diazabicyclo[5.4.0]undec-7-ene and a suitable solvent is dichloromethane. Alternatively, the base can be sodium imidazolide. An alternative method is to make a N-trialkylsilyl dervative of (III), and mix with (IV) at room temperature in tetrahydrofuran (THF) in the presence of a catalytic amount of benzenesulphonic acid (BSA).
Certain esters of formula (II, Z is C1-3 alkyloxy) wherein at least one of R1 and R2 is other than hydrogen may be conveniently obtained from the xcex1-carbanion of an ester of formula (II) wherein at least one of R1 and R2 is hydrogen by conventional C-alkylation procedures using an alkylating agent of formula (VA) or (VB):
R1Z1 or R2Z1 xe2x80x83xe2x80x83(VA)
Z2(CH2)qZ3 xe2x80x83xe2x80x83(VB),
where the (CH2)q moiety of (VB) optionally incorporates a hetero-moiety selected from O, S, SO, SO2 and NR6, and is optionally substituted by one or more optionally protected OH, and which NR6 group may be optionally protected, wherein R1 and R2 are not hydrogen, Z2 and Z3 may be the same or different and are suitable leaving groups such as chloro, bromo, iodo, C1-C4 alkanesulphonyloxy, trifluoromethanesulphonyloxy or arylsulphonyloxy (e.g. benzenesulphonyloxy or p-toluenesulphonyloxy), and q is 3, 4, 5, 6 or 7. Other conditions are outlined belowxe2x80x94sections vii) and x).
Preferably, Z2 and Z3 are selected from bromo, iodo and p-toluenesulphonyloxy.
The carbanion may be generated using an appropriate base in a suitable solvent, optionally in the presence of a phase transfer catalyst (PTC). Typical base-solvent combinations may be selected from lithium, sodium or potassium hydride, lithium, sodium or potassium bis(trimethylsilyl)amide, lithium diisopropylamide and butyllithium, potassium carbonate, sodium or potassium t-butoxide, together with toluene, ether, DMSO, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, dimethylformamide, N,N-dimethylacetamide, 1-methylpyrrolidin-2-one and any mixture thereof.
Preferably the base is sodium hydride and the solvent is dimethylformamide, optionally with tetrahydrofuran as co-solvent, or 1-methylpyrrolidin-2-one. For monoalkylation up to about a 10% excess of base is employed whilst, for dialkylation, from about 2 to about 3 molar equivalents are generally appropriate.
Typically, the carbanion is generated at about room temperature, under nitrogen, and subsequently treated with the required alkylating agent at the same temperature. Clearly, when dialkylation is required and R1 and R2 are different, the substituents may be introduced in tandem in a xe2x80x9cone-pot reactionxe2x80x9d or in separate steps.
An amine of formula (III) may be obtained by standard chemical procedures. Other amines of formula (III), when neither commercially available nor subsequently described, can be obtained either by analogy with the processes described in the Preparations section below or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
Another way of making compounds of formula (II) where ZCO is an ester moiety, is via the reaction sequence 
The appropriate sulphonyl chloride (V) is reacted with compound (IIIxe2x80x94see above) optionally in the presence of a base and in a suitable solvent. The resulting sulphonamide (VI) is reacted with a suitable base such as n-butyllithium, sodium hydride or potassium t-butoxide in a suitable anhydrous non-protic solvent to generate the carbanion xcex1 to the sulphonamide moiety, which is then reacted with for example dimethyl carbonate or methyl chloroformate, in suitable conditions, either of which reagent would give the compound (II) where Z is methoxy.
Compounds of formula (I) where R contains a free NH, NH2 and/or OH group (apart from on the hydroxamic acid moiety) may conveniently be prepared from a corresponding N- or O-protected species (VII below). As such, compounds of formula (VII) where Rp is a O- and/or N-protected version of a corresponding compound of the formula (I), are included in the scope of this invention, with regard to aspects A, B, C and D of the invention and the specific compounds of formula (I) mentioned herein, such as those mentioned in the Preparations, as appropriate, below. Suitable protection/deprotection regimes are well known in the art, such as those mentioned in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T W Greene and P G M Wuts, John Wiley and Sons Inc (1999).
Suitable OH-protecting groups and regimes include the ethers such as t-butyloxy, tri(C1-4)silyloxy, etc., and esters such as carbonates, sulphonates, C1-4 acylates, etc. mentioned by Greene and Wuts, ibid. chapter 2. Suitable NH-protecting groups and regimes can be found in Greene and Wuts, ibid. chapter 7, and include amides such as xe2x80x9cBocxe2x80x9d, amines such as benzyl, etc.
Compounds of formula (VII) may be made by methods described herein and/or by variation of methods described herein which the skilled man will appreciate are routine variations. 
An example of a suitable OH-protecting group is the triethylsilyl (TMS) group and the protection, reaction, deprotection sequence can be summarised by steps a) to c) below:
a) ClSiMe3 (1.1 equiv per OH), WSCDI (1.1 to 1.2 equiv), HOBT or HOAT (1 to 1.1 equiv),
b) NH2OH.HCl (3 equiv) in DMF/pyridine or CH2Cl2/pyridine (3/1 to 1/1) at rt for between 4 and 20 hours.
c) TMS group removed by acid work-up.
Another example of a suitable OH-protecting group is the t-butyl (tBu) group which can be carried through the synthetic process and removed in the last step of the process. An example of the route is outlined in the scheme below (in relation to the synthesis of the compound of Example 3xe2x80x94via compounds of the Preparations mentioned below). 
An example of a suitable NH-protecting group is the t-butoxycarbonyl (Boc) group. This group can be introduced in standard ways, such as those delineated in the Examples and Preparations section below. After the hydroxamic acid unit has been introduced, the Boc group can be removed for example by treatment of the N-Boc compound in methanol or dichloromethane saturated with HCl gas, at room temperature for 2 to 4 hours.
Compounds of formula (I) where R1 and/or R2, either independently or together, contain a free NH, NH2 and/or OH group (apart from on the hydroxamic acid moiety) may conveniently be prepared from a corresponding N- and/or O-protected species (XII below). As such, compounds of formula (XII) where R1p and/or R2p is a O- and/or N-protected version of a corresponding compound of the formula (I), are included in the scope of this invention, with regard to aspects A, B, C and D of the invention and the specific compounds of formula (I) mentioned herein, such as those compounds of formula (XII) mentioned in the Preparations, as appropriate, below. Suitable protection/deprotection regimes are well known in the art, such as those mentioned in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T W Greene and P G M Wuts, John Wiley and Sons Inc (1999).
Suitable OH-protecting groups and regimes include the ethers such as t-butyloxy, tri(C1-4)silyloxy, etc., and esters such as carbonates, sulphonates, C1-4 acylates, etc. mentioned by Greene and Wuts, ibid. chapter 2. Suitable NH-protecting groups and regimes can be found in Greene and Wuts, ibid. chapter 7, and include amides such as xe2x80x9cBocxe2x80x9d, amines such as benzyl, etc.
Compounds of formula (XII) may be made by methods described herein and/or by variation of methods described herein which the skilled man will appreciate are routine variations. 
An example of a suitable OH-protecting group is the trimethylsilyl (TMS) group and the protection, reaction, deprotection sequence can be summarised by steps a) to c) below:
a) ClSiMe3 (1.1 equiv per OH), WSCDI (1.1 to 1.2 equiv), HOBT or HOAT (1 to 1.1 equiv),
b) NH2OH.HCl (3 equiv) in DMF/pyridine or CH2Cl2/pyridine (3/1 to 1/1) at rt for between 4 and 20 hours.
c) TMS group removed by acid work-up.
Another example of a suitable OH-protecting group is the t-butyl (tBu) group which can be carried through the synthetic process and removed in the last step of the process. An example of the route is outlined in the scheme below (in relation to the synthesis of the compound of Example 3xe2x80x94via compounds of the Preparations mentioned below).
An example of a suitable NH-protecting group is the t-butoxycarbonyl (Boc) group. This group can be introduced in standard ways, such as those delineated in the Examples and Preparations section below. After the hydroxamic acid unit has been introduced, the Boc group can be removed for example by treatment of the N-Boc compound in methanol or dichloromethane saturated with HCl gas, at room temperature for 2 to 4 hours.
An extension of the above is where the compound of formula (I) contains a free, OH, NH and/or NH2 group in R1, R2 and R (e.g. some Examples below). In those case a suitable precursor could be the compound of formula (XIII) below: 
where the substituents are as previously defined
Compounds of formula (I) and appropriate intermediates thereto where R1 and R2 are taken together as 3,4-dihydroxycyclopentylidene can be made via the corresponding intermediary of a corresponding cyclopent-3-enylidene moiety, viz.: 
Cyclopentylidene intermediates can be epoxidised to give the corresponding epoxide using standard methods. The epoxide can be reacted in a number of different methods to give the diol product. By suitable choice of reagents, conditions etc., the skilled chemist can make diols with any desired stereochemistry, using well-known methods.
As such, compounds of the formula (VIII) and (IX) below are included in the scope of the invention, with regard to aspects A, B, C and D and also with respect to intermediates to appropriate individual compounds of formula (I) mentioned herein. 
Also included in the invention are intermediates of formula (X) and (XI, where Rp is defined as above for compounds of formula (VII) wherein P and P1 represent standard OH and 1,2-diol protecting groups mentioned in Greene and Wuts, ibid., chapter 2. P and P1 are preferably taken together and form an acetonide moiety. 
Certain specific compounds of formulae (VIII), (IX), (X) and (XI) are mentioned in the Preparations below.
Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described herein, including in the Examples and Preparations sections, which allow the compounds defined by formula (I) to be obtained, such as carrying out certain bond-forming or functional group interconversion reactions in different sequences.
Examples of the preparation of a number of intermediates and final compounds are outlined in the following synthetic schemes, where the abbreviations used are standard and well-known to the person skilled in the art. Routine variation of these routes can give all the required compounds of the invention. 
i=NaH (1.1 equiv), HOCH2CHR11xe2x80x2OR10 (1 equiv) in toluene, reflux for 2 to 5 hours
ii=n-BuLi(1.1 equiv), Bu3SnCl (1.1 equiv), THF, xe2x88x9270xc2x0 C. to room temperature. Or, Pd(PPh3)4 (0.01 to 0.05 equiv), [SnMe3]2 (1.1 equiv), dioxan, reflux for 2 to 5 hrs.
iii=BSA (0.5 equiv), MeCO2CH2SO2Cl (1.2 equiv), THF, rt for 18 hours.
iv=MeSO2Cl (1.2 equiv), Et3N (1.4 equiv), CH2Cl2, rt, for an hour.
v=Et3SiH (3 equiv), CF3SO3H (0.1 equiv), TFA:CH2Cl2 (1:1), rt, for 1-24 hrs.
vi=NaH (2 equiv), Me2CO3 (4 equiv), toluene, reflux for 2 hours.
R10-alcohol protecting groupxe2x80x94e.g. benzyl or dioxalane (for diols)
R11xe2x80x2xe2x80x94H or a protected alcohol 
vii=(VB), (1.3 equiv), K2CO3 (3 equiv), DMSO, rt, 18-24 hours, or KOtBu (2.5 equiv), (VA) or (VB) (excess), in THF, rt for 72 hours.
viii=Stille coupling-Pd(PPh3)4 (0.05 equiv), stannane(1.5 equiv), toluene, reflux for 4 to 20 hours OR PdCl2(PPh3)2 (0.05 equiv), stannane(1.1 equiv), THF, reflux for 17 hours.
ix=NH4+HCO3xe2x88x92(excess)Pd(OH)2/C, AcOH, MeOH, reflux for 20 hours, OR 10% Pd/C, in MeOH or EtOH, 3.3 atmospheres, room temperature, for 6 to 17 hours,xe2x80x94both methods also deprotect any benzyl group. (2N HCl, dioxan (3:1), rt, 75 mins at rtxe2x80x94deprotects the dioxalane)
OR Pd(OH)2/C, NH4+HCO3xe2x88x92(excess), in MeOH:dioxan (2.5:1), 60xc2x0 C. for 2 hours.
R11=H or deprotected alcohol
Similarly
when R1R2 when taken together, are a piperidine group: 
x=NaH (3 equiv), tetra-nBuNH4Br (1 equiv), BnN(CH2CH2Cl)2 (0.95 equiv), NMP, 60xc2x0 C. for 6 hours.
xi=When R12 is Me, formaldehyde(4 equiv), Na(OAc)3BH (2 equiv), CH2Cl2, 20 hrs at rt.
When R12 is Boc, (Boc)2O (1.05 equiv), Et3N (1.1 equiv), CH2Cl2, rt for an hour. 
xii=nBuLi (1.1 equiv), B[OCH(CH3)2]3 (1.5 equiv), THF, xe2x88x9270xc2x0 C. to rt.
xiii=Suzuki coupling-arylboronic acid (1.2 to 1.5 equiv), CsF(2 to 2.6 equiv), P(o-tol)3 (0.1 equiv), Pd2(dba)2 (0.005 equiv), DME, reflux for 6 to 50 hours.
xiv=Et3SiH (3 equiv), TFA:CH2Cl2 (1:1), rt for 2 to 24 hours.
xv=R/S glycidol (1 equiv), Et3N (catalytic), MeOH, reflux for 20 hours. OR, Mitsunobu reaction -DEAD(1.5 equiv), PPh3 (1.5 equiv), HOCH(R11xe2x80x2)CH2OR13xe2x80x2 (1.5 equiv) in THF, rt for 3 hours.
R11xe2x80x2 is H or optionally protected alcohol
and R13xe2x80x2 is optionally protected alcohol
For preparation 50 to 51, requires Bn deprotection using the conditions described in ix. 
xxiv=i-NaH (2.2 equiv), Me2CO3 (5 equiv), toluene, MeOH (catalytic), 90xc2x0 C., overnight. ii-O(CH2CH2Br)2 (1.3 equiv), NMP, 90xc2x0 C., 20 hrs.
xxv=Grignard reagant (1.1 equiv), THF, xe2x88x9278xc2x0 C. to rt over approx hr.
R15xe2x80x2-optionally protected alcohol, in prep 48 this is a t-butyl ether.
R15xe2x80x94OH, for prep 48. 
When R15 is a protecting group, eg. benzyl, deprotection, followed by protection using an alternative group eg Boc, can be used as shown below: 
xvi=1N HCl (1 to 2.3 equiv), acetone:dioxan (1:1), 70xc2x0 C. for 2 to 6 hours.
xvii=Reductive amination-amine (5.5 equiv), Na(OAc)3BH (3 to 4 equiv), CH2Cl2, rt, overnight.
xviii=Pd(OH)2/C, MeOH, 50 psi, rt, 18 hrs.
xix=When R16 is Boc, (Boc)2O (1 to 1.1 equiv), Et3N (optional, 1 equiv), DMAP (optional, cat), CH2Cl2, rt, 3 hrs. 
xx=iso-PrSO2Cl (1 equiv), Et3N (1.1 equiv), CH2Cl2, 3 hours at rt.
xxi=n-BuLi (1.1 equiv), MeOCOCl (1.2 equiv), THF xe2x88x9278xc2x0 to rt.
xxii=2,6-di-t-Bu-4-Me pyridine (2.5 equiv), (CF3SO2)2O (2.5 equiv), CH2Cl2, 4xc2x0 C. to rt, 5 days.
xxiii=Pd2(dba)3 (0.02 equiv), vinyl triflate (1.1 equiv), Ph3As (0.21 equiv), CuI (0.1 equiv) in NMP, 75xc2x0 C. for 5 hrs. 
xxvi=NaH (1.1 equiv), tetra-nBuNH4Br (1 equiv), ClCH2CHCHCH2Cl (1.1 equiv), NMP, r.t for 3 hours, then NaH (1.1 equiv), 2 days.
xxvii=NMO (1.1 equiv), OsO4 (3 mol%), dioxan/water, r.t. 18 hours OR
(a) AgOAc (2.3 equiv), AcOH, r.t for 18 hours (b) 1N NaOH, dixoan/water
xxviii=2,2-Dimethoxypropane (2 equiv), TsOH (0.1 equiv), DMF, 50xc2x0 C. for 4.5 hours.
The biological activities of the compounds of the present invention were determined by the following test methods, which are based on the ability of the compounds to inhibit the cleavage of various fluorogenic peptides by MMPs 1, 2, 3, 9, 13 and 14.
The assays for MMPs 2, 3, 9 and 14 are based upon the original protocol described in Fed. Euro. Biochem. Soc., 1992, 296, 263, with the minor modifications described below.
Inhibition of MMP-1
Enzyme Preparation
Catalytic domain MMP-1 was prepared in Pfizer Central Research laboratories in a standard manner from sources known to the skilled person, including some of the references mentioned herein. A stock solution of MMP-1 (1 xcexcM) was activiated by the addition of aminophenylmercuric acetate (APMA), at a final concentration of 1 mM, for 20 minutes at 37xc2x0 C. MMP-1 was then diluted in Tris-HCl assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl2, 20 xcexcM ZnSO4 and 0.05% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assay was 1 nM.
Substrate
The fluorogenic substrate used in this assay was Dnp-Pro-xcex2-cyclohexyl-Ala-Gly-Cys(Me)-His-Ala-Lys-(N-Me-Ala)-NH2 as originally described in Anal. Biochem., 1993, 212, 58. The final substrate concentration used in the assay was 10 xcexcM.
Determination of Enzyme Inhibition
The test compound was dissolved in dimethyl sulphoxide and diluted with assay buffer so that no more than 1% dimethyl sulphoxide was present. Test compound and enzyme were added to each well of a 96 well plate and allowed to equilibrate for 15 minutes at 37xc2x0 C. in an orbital shaker prior to the addition of substrate. Plates were then incubated for 1 hour at 37xc2x0 C. prior to determination of fluorescence (substrate cleavage) using a fluorimeter (Fluostar; BMG LabTechnologies, Aylesbury, UK) at an excitation wavelength of 355 nm and emission wavelength of 440 nm. The potency of inhibition was measured from the amount of substrate cleavage obtained using a range of test compound concentrations and, from the resulting dose-response curve, an IC50, value (the concentration of inhibitor required to inhibit 50% of the enzyme activity) was calculated.
Inhibition of MMP-2, MMP-3 and MMP-9
Enzyme Preparation
Catalytic domains MMP-2, MMP-3 and MMP-9 were prepared in Pfizer Central Research laboratories in a standard manner from sources known to the skilled person, including some of the references mentioned herein. A stock solution of MMP-2, MMP-3 or MMP-9 (1 xcexcM) was activated by the addition of APMA. For MMP-2 and MMP-9, a final concentration of 1 mM APMA was added, followed by incubation for 1 hour at 37xc2x0 C. MMP-3 was activated by the addition of 2 mM APMA, followed by incubation for 3 hours at 37xc2x0 C. The enzymes were then diluted in Tris-HCl assay buffer (100 mM Tris, 100 mM NaCl, 10 mM CaCl2 and 0.16% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assays was 1 nM.
Substrate
The fluorogenic substrate used in this screen was Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2 (Bachem Ltd., Essex, UK) as originally described in J. Biol. Chem., 1994, 269, 20952. This substrate was selected because it has a balanced hydrolysis rate against MMPs 2, 3 and 9 (kcat/km of 54,000, 59,400 and 55,300 sxe2x88x921 Mxe2x88x921 respectively). The final substrate concentration used in the assay was 5 xcexcM.
Determination of Enzyme Inhibition
The test compound was dissolved in dimethyl sulphoxide and diluted with assay buffer so that no more than 1% dimethyl sulphoxide was present. Test compound and enzyme were added to each well of a 96 well plate and allowed to equilibrate for 15 minutes at 37xc2x0 C. in an orbital shaker prior to the addition of substrate. Plates were then incubated for 1 hour at 37xc2x0 C., prior to determination of fluorescence using a fluorimeter (Fluostar; BMG LabTechnologies, Aylesbury, UK) at an excitation wavelength of 328 nm and emission wavelength of 393 nm. The potency of inhibition was measured from the amount of substrate cleavage obtained using a range of test compound concentrations and, from the resulting dose-response curve, an IC50 value (the concentration of inhibitor required to inhibit 50% of the enzyme activity) was calculated.
Inhibition of MMP-13
Enzyme Preparation
Human recombinant MMP-13 was prepared by PanVera Corporation (Madison, Wis.) and characterised at Pfizer Central Research laboratories. A 1.9 mg/ml stock solution was activated with 2 mM APMA for 2 hours at 37xc2x0 C. MMP-13 was then diluted in assay buffer (50 mM Tris, 200 mM NaCl, 5 mM CaCl2, 20 xcexcM ZnCl2 and 0.02% Brij 35, pH 7.5) to a concentration of 5.3 nM. The final concentration of enzyme used in the assay was 1.3 nM.
Substrate
The fluorogenic substrate used in this screen was Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2. The final substrate concentration used in the assay was 10 xcexcM.
Determination of Enzyme Inhibition
The test compound was dissolved in dimethyl sulphoxide and diluted with assay buffer so that no more than 1% dimethyl sulphoxide was present. Test compound and enzyme were added to each well of a 96 well plate. The addition of substrate to each well initiated the reaction. Fluorescence intensity was determined using a 96 well plate fluorimeter (Cytofluor II; PerSeptive Biosystems, Inc., Framingham, Mass.) at an excitation wavelength of 360 nm and emission wavelength of 460 nm. The potency of inhibition was measured from the amount of substrate cleavage obtained using a range of test compound concentrations and, from the resulting dose-response curve, an IC50 value (the concentration of inhibitor required to inhibit 50% of the enzyme activity) was calculated.
Inhibition of MMP-14
Enzyme Preparation
Catalytic domain MMP-14 was prepared in Pfizer Central Research laboratories in a standard manner from sources known to the skilled person, including some of the references mentioned herein. A 10 xcexcM enzyme stock solution was activated for 20 minutes at 25xc2x0 C. following the addition of 5 xcexcg/ml of trypsin (Sigma, Dorset, UK). The trypsin activity was then neutralised by the addition of 50 xcexcg/ml of soyabean trypsin inhibitor (Sigma, Dorset, UK), prior to dilution of this enzyme stock solution in Tris-HCl assay buffer (100 mM Tris, 100 mM NaCl, 10 mM CaCl2, 0.16% Brij 35, pH 7.5) to a concentration of 10 nM. The final concentration of enzyme used in the assay was 1 nM.
Substrate
The fluorogenic substrate used in this screen was Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Bachem Ltd., Essex, UK) as described in J. Biol. Chem., 1996, 271, 17119.
Determination of enzyme inhibition
This was performed in the same manner as described for MMPs 2, 3 and 9.
For use in mammals, including humans, the compounds of formula (I) or their salts or solvates of such compounds or salts, can be administered alone, but will generally be administered in admixture with a pharmaceutically or veterinarily acceptable diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally, including sublingually, in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. The compound or salt could be incorporated into capsules or tablets for targetting the colon or duodenum via delayed dissolution of said capsules or tablets for a particular time following oral administration. Dissolution could be controlled by susceptibility of the formulation to bacteria found in the duodenum or colon, so that no substantial dissolution takes places before reaching the target area of the gastrointestinal tract. The compounds or salts can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution or suspension which may contain other substances, for example, enough salt or glucose to make the solution isotonic with blood. They can be administered topically, in the form of sterile creams, gels, suspensions, lotions, ointments, dusting powders, sprays, drug-incorporated dressings or via a skin patch. For example they can be incorporated into a cream consisting of an aqueous or oily emulsion of polyethylene glycols or liquid paraffin, or they can be incorporated into an ointment consisting of a white wax soft paraffin base, or as hydrogel with cellulose or polyacrylate derivatives or other viscosity modifiers, or as a dry powder or liquid spray or aerosol with butane/propane, HFA or CFC propellants, or as a drug-incorporated dressing either as a tulle dressing, with white soft paraffin or polyethylene glycols impregnated gauze dressings or with hydrogel, hydrocolloid, alginate or film dressings. The compound or salt could also be administered intraocularly as an eye drop with appropriate buffers, viscosity modifiers (e.g. cellulose derivatives), preservatives (e.g. benzalkonium chloride (BZK)) and agents to adjust tenicity (e.g. sodium chloride). Such formulation techniques are well-known in the art. In some instances the formulations may advantageously also contain an antibiotic. All such formulations may also contain appropriate stabilisers and preservatives.
For veterinary use, a compound of formula (I), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Reference to treatment includes prophylaxis as well as alleviation of established conditions, or the symptoms thereof.
For oral and parenteral administration to animal (inc. human) patients, the daily dosage level of the compounds of formula (I) or their salts will be from 0.001 to 20, preferably from 0.01 to 20, more preferably from 0.1 to 10, and most preferably from 0.5 to 5 mg/kg (in single or divided doses). Thus tablets or capsules of the compounds will contain from 0.1 to 500, preferably from 50 to 200, mg of active compound for administration singly or two or more at a time as appropriate.
For topical administration to animal (inc. human) patients with chronic wounds, the daily dosage level of the compounds, in suspension or other formulation, could be from 0.001 to 30mg/ml, preferably from 0.01 to 10 mg/ml.
The physician or veterinary surgeon in any event will determine the actual dosage which will be most suitable for a an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Thus the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.
The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or solvate thereof, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament.
In yet another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a human medicament for the treatment of a condition mediated by one or more MMPs.
Moreover, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a human medicament for the treatment of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wounds, skin diseases, cancer metastasis, tumour angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells.
Additionally, the invention provides a method of treating a medical condition for which a MMP inhibitor is indicated, in an animal such as a mammal (including a human being), which comprises administering to said animal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing.
Still further, the invention provides a method of treating atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wounds, skin diseases, cancer metastasis, tumour angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells, in a animal (including a human being), which comprises administering to said animal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing.
Biological data
The compounds of Examples 3, 4, 5, 6, 7, 10 and 14 gave the following IC50 values (in nM concentrations) in tests mentioned above: